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Recurring Pregnancy Loss

Recurrent miscarriage is a distressing problem that affects 1% of all women.
Recurrent miscarriage is defined as the loss of three or more pregnancies. Recurrent miscarriage is a heterogeneous condition that has many possible causes; more than one contributory factor may underlie the recurrent pregnancy losses.
Maternal age and previous number of miscarriages are two independent risk factors for a further miscarriage. Advanced maternal age adversely affects ovarian function, giving rise to a decline in the number of good quality oocytes, resulting in chromosomally abnormal conceptions that rarely develop further.

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Investigations and treatments

1. Genetic factor:

All couples with a history of recurrent miscarriage should have peripheral blood karyotyping performed. In approximately 3–5% of couples with recurrent miscarriage, one of the partners carries a balanced structural chromosomal anomaly. The most common types of parental chromosomal abnormality are balanced reciprocal or Robertsonian translocations. Genetic counseling offers the couple a prognosis for future pregnancy, familial chromosomal studies, counseling and appropriate prenatal diagnosis in future pregnancies where there is a 5–10% chance of a pregnancy with an unbalanced translocation. In all couples with a history of recurrent miscarriage cytogenetic analysis of the products of conception should be performed if the next pregnancy fails.
Recurrent pregnancy loss may be due to an abnormal embryo, which is incompatible with life, e.g. chromosomal abnormalities or structural malformations. As the number of miscarriages increases, the prevalence of chromosomal abnormality decreases and the chance of recurring maternal cause increases. If the karyotype of the miscarried pregnancy is abnormal, there is a better prognosis in the next pregnancy.Cytogenetic testing is an expensive tool and may be reserved for patients who have undergone treatment in the index pregnancy or have been participants in a research trial; for them, karyotyping the products of conception provides useful information for counseling and future management.

2. Anatomical factors

It is difficult to assess the exact contribution that congenital uterine anomalies make to recurrent pregnancy loss. The reported prevalence of uterine anomalies in recurrent miscarriage population’s range is between 2% and 40%.
The prevalence of uterine malformations appears to be higher in women with late miscarriages compared with women who suffer early miscarriages but this may be related to the cervical weakness that is frequently associated with uterine malformation.Open uterine surgery is associated with postoperative infertility and carries a significant risk of uterine scar rupture during pregnancy.

The routine use of hysterosalpingography along with 3 D/4D uterine evaluation as a screening test for uterine anomalies in women with recurrent miscarriage is a GOOD and COST EFFECTIVE option in comparison to endoscopy.

We also offer -Non-invasive two or three dimensional pelvic ultrasound assessment of the uterine cavity with (or without) Sonohysterography (SSG or HyCoSy) , which is also a good option.
The diagnostic value of three-dimensional ultrasound has been explored and appears promising.Since three-dimensional ultrasound offer both diagnosis and classification of uterine malformation its use may obviate the need for diagnostic hysteroscopy and laparoscopy.
All women with recurrent miscarriage should have a pelvic ultrasound to assess uterine anatomy and morphology.

3. Cervical weaknesses

Cervical weakness is often a cause of mid-trimester miscarriage.
There is currently no satisfactory objective test that can identify women with cervical weakness in the non-pregnant state. The diagnosis is usually based on a history of late miscarriage, preceded by spontaneous rupture of membranes or painless cervical dilatation.
Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness.
Trial of elective cervical cerclage reported a small decrease in preterm birth and delivery of very-low- birthweight babies, but the benefit was most marked in women with two or more second-trimester miscarriages or preterm births.
Transabdominal cerclage has been advocated as a treatment for second-trimester miscarriage and the prevention of early preterm labour in selected women with previous failed transvaginal cerclage and/or a very short and scarred cervix.

4. Endocrine factors

Routine screening for occult diabetes and thyroid disease with oral glucose tolerance and thyroid function tests in asymptomatic women presenting with recurrent miscarriage may be helpful.
Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been associated with miscarriage.
Women with diabetes who have high hemoglobin A1c levels in the first trimester are at risk of miscarriage and fetal malformation.
There is sufficient evidence to use progesterone or HCG supplementation in pregnancy to prevent a miscarriage.
Polycystic ovarian syndrome (PCOS) has been linked to miscarriage. LH hypersecretion, a frequent feature of PCOS, has been reported as a risk factor for early pregnancy loss.
Polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.
Polycystic ovary morphology is a classical feature of PCOS. The prevalence of polycystic ovaries, identified using pelvic ultrasound criteria, is significantly higher among women with recurrent miscarriage (41%) when compared with the general population (22%).
A history of subfertility (conception delay greater than 12 months) is present in 25–30% of women with recurrent miscarriage. It is most frequently due to ovulatory disorders and confers a poor prognosis for future pregnancy outcome.
Persistently raised follicle-stimulating hormone levels are found in a small percentage of these women and this should prompt further investigation and counseling for the implications of premature ovarian failure.
There are few evidences to assess the effect of hyperprolactinemia as a risk factor for recurrent miscarriage.

5. Immune factors

Routine screening for thyroid antibodies in women with recurrent miscarriage is not recommended.

Antiphospholipid syndrome

Primary antiphospholipid syndrome (APS) refers to the association between antiphospholipid antibodies (aPL) and adverse pregnancy outcome or vascular thrombosis.
Adverse pregnancy outcomes include (a) three or more consecutive miscarriages before ten weeks of gestation, (b) one or more morphologically normal fetal deaths after the tenth week of gestation and (c) one or more preterm births before the 34thweek of gestation due to severe pre-eclampsia, eclampsia or placental insufficiency.
Where APS exists in chronic inflammatory disorders, such as systemic lupus erythematosus, it is referred as secondary APS.
The mechanisms by which aPL causes pregnancy morbidity include inhibition of trophoblastic function and differentiation and, in later pregnancy, thrombosis of the uteroplacental vasculature.
To diagnose APS it is mandatory that the patient should have two positive tests at least six weeks apart for either lupus anticoagulant or anticardiolipin (aCL) antibodies of IgG and/or IgM class present.
In detection of lupus anticoagulant, the dilute Russell’s viper venom time (dRVVT) test is more sensitive and specific than either the activated partial thromboplastin time (aPTT) or the kaolin clotting time (KCL) tests.Anticardiolipin antibodies are detected using a standardised enzyme- linked immunosorbent assay (ELISA). The detection of aPL is subject to considerable inter- laboratory variation.
Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage.By comparison, the prevalence of aPL in women with a low risk obstetric history is less than 2%.In women with recurrent miscarriage associated with aPL, the live birth rate in pregnancies with no pharmacological intervention may be as low as 10%.Controlled trials have reported that treating women who suffer recurrent miscarriage associated with aPL with steroid therapy during pregnancy does not improve the live birth rate when compared with aspirin or aspirin plus heparin. Steroid therapy is associated with significant maternal and fetal morbidity.In women with a history of recurrent miscarriage and aPL, future live birth rate is significantly improved when a combination therapy of aspirin plus heparin is prescribed.
Live birth rate of women with recurrent miscarriage associated with aPL treated with low-dose aspirin only is 40% and this is significantly improved to 70% when they are treated with low-dose aspirin in combination with low-dose heparin.In women with a history of recurrent miscarriage associated with aPL, treatment with low-dose heparin plus low-dose aspirin significantly reduced the pregnancy losses by 54% when compared with aspirin alone.
A recent randomized controlled trial reported a high success rate with aspirin alone and no significant benefit in live birth rate with the addition of heparin. Pregnancies associated with aPL treated with aspirin and heparin remain at high risk of complications during all three trimesters.
Although aspirin plus heparin treatment substantially improves the live birth rate of women with recurrent miscarriage associated with aPL, these pregnancies remain at high risk of complications during the three trimesters including repeated miscarriage, pre-eclampsia, fetal growth restriction and preterm birth,necessitating careful antenatal surveillance.

Alloimmune factors

Immunotherapy, including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes and intravenous immunoglobulin (IVIG), in women with previous unexplained recurrent miscarriage does not improve the live birth rate.

Infective agents

TORCH (toxoplasmosis, other [congenital syphilis and viruses], rubella, cytomegalo- virus and herpes simplex virus) screening may be helpful in the investigation of recurrent miscarriage.
Any severe infection that leads to bacteraemia or viraemia can cause sporadic miscarriage. The role of infection in recurrent miscarriage is unclear.
Screening for and treatment of bacterial vaginosis in early pregnancy among high risk women with a previous history of second-trimester miscarriage or spontaneous preterm labour may reduce the risk of recurrent late loss and preterm birth.
The presence of bacterial vaginosis in the first trimester of pregnancy has been reported as a risk factor for second-trimester miscarriage and preterm delivery but the evidence for an association with first-trimester miscarriage is inconsistent.For women with a history of previous preterm birth, detection and treatment of bacterial vaginosis early in pregnancy may prevent a further preterm birth.

6. Inherited thrombophilic defects

Inherited thrombophilic defects, including activated protein C resistance (most commonly due to factor V Leiden gene mutation), deficiencies of protein C/S and antithrombin III, hyperhomocysteinaemia and prothrombin gene mutation, are established causes of systemic thrombosis.
Retrospective studies have suggested an association between inherited thrombophilic defects and fetal loss and late pregnancy complications, with a presumed mechanism being thrombosis of uteroplacental circulation.
The efficacy of thromboprophylaxis during pregnancy in women with recurrent miscarriage who have inherited thrombophilic defects, but who are otherwise asymptomatic, has not been assessed in prospective randomized controlled trials.
Heparin therapy may improve the live birth rate for these women.

7. Unexplained recurrent miscarriage

Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome, may be without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit.
A significant proportion of cases of recurrent miscarriage remain unexplained, despite detailed investigation. These women can be reassured that the prognosis for a successful future pregnancy with supportive care alone is in the region of 75%.However, the prognosis worsens with increasing maternal age and the number of previous miscarriages. The value of psychological support in improving pregnancy outcome has not been tested in the form of a randomized controlled trial.
Use of empirical treatment in women with unexplained recurrent miscarriage is unnecessary and but it will give a good mental support and may be good placebo effect!
Further, clinical evaluation of future treatments for recurrent miscarriage should only be performed in the context of randomized trials that are suitably matched and corrected to exclude fetal chromosomal aberrations.